Certain 4-(n-pyrimidin-2-ylsulfamoyl)-phenylacetamides

ABSTRACT

Compounds of the formula   WHEREIN R is 1-tetrahydronaphthyl, 1-indanyl, 1- Alpha -naphthylethyl, 1-(2-pyridyl)-etheyl, 1-phenyl-2,2,2-trifluoroethyl, 1cyanobenzyl, 1-(2-phenyl)-phenylethyl, or 1-(N-methyl-3indolyl)-ethyl; R&#39;&#39; is hydrogen; or R and R&#39;&#39; jointly with the connecting nitrogen atom are 2methylindolyl; and R&#39;&#39;&#39;&#39; is isobutyl, neopentyl, or i-propoxy, AND THEIR SALTS WITH PHYSIOLOGICALLY TOLERATED BASES LOWER THE BLOOD SUGAR LEVEL IN DIABETES MELLITUS.

United States Patent [191 Ahrens et al.

[451 Apr. 15, 1975 CERTAIN 4-(N-PYRIMlDIN-2-YLSULFAMOYL)- PHENYLACETAMIDES [76] Inventors: Hanns Ahrens, Spanische Allee 72a,

1 Berlin 38; Helmut Biere, Joachim-Friedrich-Str. 13, 1 Berlin 31; Clemens Rufer, 38 Lagardestr. 44a, 1 Berlin 38; Wolfgang Felix Losert, Maximilankorso 20, 1 Berlin 28; Olaf Loge, Hauptstr. 118, 1 Berlin 62; Ekkehard Schillinger, Bekassinenweg, 37, 1 Berlin 27; Eberhard Schriider, Am Rosenanger 22, Berlin 28; Erich Gerhards, Cimbernstr. 6, Berlin 38, all of Germany 9 [22] Filed: Sept. 13, 1972 [21] Appl. No.: 288,590

Related US. Application Data [63] Continuation-in-part of Ser. No. 129,948, March 31,

1971, abandoned.

[30] Foreign Application Priority Data Oct. 5, 1971 Germany 2150279 [52] US. Cl 260/256.5 R; 260/247.1; 424/251 [51] Int. Cl C07d 51/42 [58] Field of Search 260/256.5 R

[56] References Cited UNITED STATES PATENTS 3,621,026 11/1971 Gutsche et al. 260/256.5 R

Primary ExaminerR. J. Gallagher Attorney, Agent, or Firm-Joseph F. Padlon [57] ABSTRACT Compounds of the formula N-CO-C Rl/ a SOZ-NH- N R".

wherein R is l-tetrahydronaphthyl, 1 -indan yl, l-a-naphthylethyl, l-(2-pyridyl)-etheyl, l-phenyl-2,2,Z-trifluoroethyl, l-cyanobenzyl, 1-( 2-phenyl )-phenylethyl, or l-(N-methyl-3-indolyl)-ethyl;

R is hydrogen; or

R and R jointly with the connecting nitrogen atom are 2-methylindolyl; and

R" is isobutyl, neopentyl, or i-propoxy,

and their salts with physiologically tolerated bases lower the blood sugar level in diabetes mellitus.

13 Claims, N0 Drawings CERTAIN 4-(NJZYRIDIMIN-2-YLSULFAMOYL)- I PHENYLACETAMIDES This application.isa'continuation in part of our copending application Ser. No. 129,948 filed Mar. 31, 1971 now abandoned.

In the parent application Ser. No; 129,948, there were disclosed compounds of the formula wherein:

C* is an axymmetric carbon atom,

A is a monocyclic aromatic ring which may contain two substitutents R and R X and Y are equal or different and each constitute a direct bond or methylene,

R and R are different and are hydrogen, straightchained or branched alkyl having up to 4 carbon atoms, carboxyl or alkoxycarbonyl having up to 4 carbon atoms in the alkoxy group, R and R are equal or different and are hydrogen or alkyl having up to 4 carbon atoms, R is straight chained or branched alkyl having up to 6 carbon atoms, and

W is a direct CC bond, oxygen, or sulfur, and their salts with physiologically tolerated bases.

These compounds are suitable for treatment of diabetes mellitus.

It has now been found that a strong lowering effect on the blood sugar level is also produced by sulfamoylpyrimidines of the formula wherein I R is l-tetrahydronaphthyl, l-indanyl, l-anaphthylethyl, l-(2-pyridyl)-ethyl, 1-phenyl-2,2,2-

trifluoroethyl, l-cyanobenzyl, 1-(2-phenyl)- I phenylethyl, or 1-(N-methyl-3-indolyl)-ethyl;

R is hydrogen; or

R and R jointly with the connecting nitrogen atom are 2-methylindoyl; and

R is isobutyl neopentyl or i-propoxy, and salts of said sulfamoylpyrimidines with physiologically tolerated bases.

The tests for blood sugar level is performed hourly for six hours on a rabbit having fasted for 24 hours. The lowest dosage, for example of 4-[N-(5-isobutyl-2- pyrimidinyl)-sulfamoyl]-phenylacetic acid l-anaphthylethylamide which lowers the blood sugar level as strongly as 1 mg/kg 4-[N-(5-isopropoxy-2- pyrimidinyl)-sulfamoyl]-phenylacetic acid 5-chloro-2- methoxyanilide, one of the most effective compounds. disclosed in Belgian Patent No. 726,253, is near 3 for the form, and near 0.1 for the form (tested dosage levels being: 30, 3, 1, 05,025, 0.1 0.05 mg/kg). It is surprisingjthat the increase in the blood sugar ilevel lowering effect is broug'ht'about by achange "of the molecule in the extended side chain of the sulfonated benz'ene nucleus, that is, in a location which does not necessarily relate to the fi-zytotrop'ic effect of the sulfonamides, since even compounds having no side chains, such as Glymidin, have B-zytotropic effect.

For their therapeutic use, the compounds of the invention may be administered orally as the free sulfonamides, as salts with physiologically tolerated inorganic and/or organic bases, such as sodium, lithium, calcium, ammonium hydroxides, amines such as methylglucamine, morpholine, ethanolamine, and the like, also in the form of mixtures of the free sulfonamides with a suitable alkali metal carbonate or bicarbonate. Bases which themselves lower the blood sugar level, such as EXAMPLE 1 4-'[N-(S-Isobutyl-Z-pyrimidinyl)-sulfamoyl]- phenylacetic acid l-tetrahyd ronaphthylam ide A solution of 22 millimole (mM) triethylamine and 22 mM l-aminotetrahydronaphthalene in 30 ml acetone was added dropwise to a solution of 20 mM 4-[N- (5-isobutyl-2-pyrimidinyl)-sulfamoyl]-phenylacetyl chloride in m1 acetone. The'mixt'ure was held for 16 hours at 20 C, then heated to a boil for minutes, cooled, and filtered with suction. The recovered solid was recrystallized from ethanol.

Yield: 4.5 g of melting point 174 C.

EXAMPLE 2 4-[N-(5-lsobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid l-indanylamide The compound was prepared in a manner analogous to Example 1 from l-aminoindane. Yield: 5.8 g of melting point 154 C.

. EXAMPLE 3 R(+)-4-[N-(5-Isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid l-a-naphthylethylamide The compound was prepared as in Example 1 using R(+)-l-a-naphthylethylamine, and recrystallized from acetone-water mixture 1:1.

Yield: 3.7 g of melting point 172 C. [0:]D +27 (c=l, chloroform).

EXAMPLE 4 S(-)-4-N -(5-Isobutyl-Z-pyrimidinyl)-sulfamoyl]- phenylacetic acid l-a-naphthylethylamide The compound was prepared as in Example 1 from S()-l-a-naphthylethylamine, and recrystallized from actone/water mixture 1 :1

Yield: 4.0 g of melting point 172 C. [011D 23.7 (c=l, chloroform).

EXAMPLE l-a-naphthylethylamide 2-Amino-5-neopentylpyrimidine was prepared by a procedure generally known for synthesizing 2-amino-5- alkylpyrimidines (Arzneimittelforschung 14 [1964 ]373).

56 Millimoles of the prepared compound were treated with 4-chlorosulfonyl-phenylacetic acid in 100 ml pyridin for 2 hours at 80 C. Aqueous hydrochloric acid was added to form a precipitate in which the dimethylamide moiety was saponified by means of 3% sodium hydroxide solution in 6 hours at a boil. The saponification mixture was filtered hot, and 4-[N-(5- neopentyl-Z-pyrimidinyl)-sulfamoyl]-phenylacetic acid was precipitated with hydrochloric acid from the filtrate and recrystallized from methylglycol/ethanol mixture. It weighed 14.2 g and melted at 250 C. The acid was converted to the acyl chloride with thionyl chloride, and 19 mM of the acyl chloride were reacted with 28 mM (S)-la-naphthylethylamine and 20 mM triethylamine in 100 ml chloroform at boiling heat in 1 hour. The solvent was evaporated, the residue was suspended in dilute hydrochloric acid, and sequentially recrystallized from pyriding-water mixture and isopropanolacetone-water.

The desired product was ultimately obtained in a yield of 46% and melted at 166 C. [a]D 25 (c=l, chloroform).

EXAMPLE 6 S()-4[N-('5-Isopropoxy-2-pyrimidinyl )-sulfamoyl]- phenylacetic acid l-a-naphthylethylamide phenylacetyl chloride and (S)-l-a-naphthylethylamine.

Yield: 43% of theory. Melting point: 183 C.

EXAMPLE 7 4-[ N-( 5 -lsobutyl-2-p yrimidinyl )-sulfamoyl 1- phenylacetic acid+l 2-pyridyl)-ethylamide The compound was prepared by analogy with Example 1 from l-(2-pyridyl)-ethylamine. However, the ace tone was distilled off, the residue was suspended in dilute hydrochloric acid and extracted with chloroform. The residue obtained after evaporation of the chloroform was taken up in aqueous sodium bicarbonate solution, the mixture was filtered, the filtrate was acidified, and the precipitate formed thereby was filtered off with suction and taken up in aqueous ammonia. The solution was filtered over charcoal and acidified to pH 6 with 20% acetic acid. The precipitate was recrystallized from ethanol-water.

Yield: 1.2 g containing 1.4% water. Melting point: 84 C.

EXAMPLE 8 4-[N-(5-Isobutyl-2-pyrimidiny1)-sulfamoyl]- phenylacetic acid 1 -phenyl-2-2,2-trifluoroethylamide The compound was prepared by analogy with Example 1 using 1-phenyl-2,2,2-trifluoroethylamine. Yield; 30% of theory. melting point: 168 C.

EXAMPLE 9 4-[N-(5-Isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid l-cyanobenzylamide The compound was prepared from 2-phenylglycine nitrile by analogy with Example 1. Yield: 13% of theory. Melting Point: C.

EXAMPLE l0 4-[N-(5-Isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid l-(2-phenyl)-phenylethylamide EXAMPLE 1 l 4-[N-(5-Neopentyl-2-pyrimidinyl )-sulfamoyl]- phenylacetic acid 1-(N-methyl-3-indolyl)-ethylamide The compound was prepared according to Example 1 from l-(l-methyl-3-indolyl)-ethylamine.

EXAMPLE l2 4-[N-(5-Isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid 2-methylindolinide The compound was prepared according to Example 1 from Z-methylindoline. Yield: 40% of theory. Melting point: 171 C (hydrate).

We claim:

1. A compound which is a sulfamoylpyrimidine of the formula wherein R is l-tetrahydronaphthyl, l-indanyl, l-anaphthylethyl, l-(2-pyridyl)-ethyl, l-phenyl-2,2,2- trifluoroethyl, l-cyanobenzyl, l-( 2-phenyl)- phenylethyl, or l-(N-methyl-3-indolyl)-ethyl; R is hydrogen, or R and R jointly with the connecting nitrogen atom are Z-methylindolyl; and R" is isobutyl, neopentyl, or isopropoxy; or a salt of said sulfamoylpyrimidine with a physiologically tolerated base.

2. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is 4-[N-(5-Isobutyl-2- pyrimidinyl)-sulfamoyl]-phenylacetic dronaphthylamide.

3. A compound as set forth in claim 1, wherein said acid- 1 -tetrahysulfamoylpy rimidine is 4-[ N 5-lsobutyl-2- pyrimidinyl )-sulfamoyll-phenylacetic acid 1- indanylamide.

4. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is R(+)-4-[N-(5-lsobutyl -2- pyrimidinyl)-sulfamoyl]-phenylacetic acid- 1 -oznaphthylethylamide.

5. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is ,S(-)-4-[N-(5-Isobutyl-2- pyrimidinyl)-sulfamoyl]-phenylacetic acidl -oznaphthylethylamide.

6 pyrimidinyl )-sulfamoyl] -phenylacetic pyridyl)-ethylamide.

9. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is 4-[N-(5-lsobutyl-2- pyrimidin yl )-sulfamoyl -phenylacetic acid- 1 -p henyl- 2,2,2-trifluoroethylamide.

10. A compound as set forth in claim 1, wherein said acid- 1 2- sulfamoylpyrimidine is 4-[N-( 5-Isobutyl-2- pyrimidinyl)-sulfamoyl]-phenylacetic acid-l-cyanobenzylamide.

11. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is 4-[N-(5-lsobutyl-2- pyrimidinyl)-sulfamoyl]-phenylacetic acid l-(2- phenyl)-phenylethylamide.

12. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is 4-[N-(5-Neopentyl-2- pyrimidinyl)-sulfamoyl]-phenylacetic acid l-(N- methyl-3-indolyl )-ethylamide.

13. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is 4- N-( 5 -lsobutyl-2- pyrimidinyl )-sulfamoyl -phenylacetic acid 2 methylindolinide. 

1. A COMPOUND WHICH IS A SULFAMOYLPYRIMIDINE OF THE FORMULA
 2. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is 4-(N-(5-Isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-tetrahydronaphthylamide.
 3. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is 4-(N-(5-Isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid 1-indanylamide.
 4. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is R(+)-4-(N-(5-Isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1- Alpha -naphthylethylamide.
 5. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is S(-)-4-(N-(5-Isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1- Alpha -naphthylethylamide.
 6. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is S(-)-4-(N-(5-Neopentyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1- Alpha -naphthylethylamide.
 7. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is S(-)-4-(N-(5-Isopropoxy-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1- Alpha -naphthylethylamide.
 8. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is 4-(N-(5-Isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-(2-pyridyl)-ethylamide.
 9. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is 4-(N-(5-Isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-phenyl-2,2,2-trifluoroethylamide.
 10. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is 4-(N-(5-Isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-cyano-benzylamide.
 11. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is 4-(N-(5-Isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid 1-(2-phenyl)-phenylethylamide.
 12. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is 4-(N-(5-Neopentyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid 1-(N-methyl-3-indolyl)-ethylamide.
 13. A compound as set forth in claim 1, wherein said sulfamoylpyrimidine is 4-(N-(5-Isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid 2''-methylindolinide. 